Cyclopentanophenanthrene compounds and process



United States CYCLOPENTANOPHENAN'IHRENE COMPOUNDS AND PROCESS Jesus Rome and George, Rosenkranz, Mexico City, Mexico, and Carl Djera's'si, Detroit, Mich., assignors to Syntex S. A., Mexico City, Mexico, a corporation of Mexico No Drawing. Applicj ation'May 16, 1952, Serial No. 288,312

Claims priority, application Mexico May 25, 1951 10 Claims. (Cl. 260-3971) The present application relates to cyclopentanophenanthrene compounds and a process for producing the same. More particularly the present invention relates to a novel process for selectively removing the l6-double bond in A compounds of the pregnene series without altering other double bonds in the nucleus.

In United States application Serial No. 206,726, filed January 18, 1951, there is disclosed a process for the reaction of (2,;3-1111Sflil1l2li6d steroid k'etones with mercaptans and to novel derivatives produced thereby. In particular i h above ap l at o t e i d losedthe reaction of pregnene derivatives such as A -pregna-. diene-3,20-dione (16-dehydroprogesterone) and 13 pregnadiene-3fi-ol-20-one 3 a'ceta'te"'(l6-dehydropregnenolone acetate) with mercaptans to form the corresponding 16 thiobenzyl compounds. w

In accordance with ,the preseiityi entionit has been found that these 16 thiobe'n'zyl dr'ivafives'ean be trans formed into the corresponding 16;.saturated steroid by removing the 16 thio grouping as by refluxing with Raney nickel catalyst.

It has been further discovered in accordance with the present invention that the mercaptans fi-mercaptoethanol and thioglycolic acid are especially suitable for the production in high yield of 16 thioderivatives which are especially useful intermediates for the production of hormones.

The removal of the 16 thio group in accordance with the present invention may be exemplified by the following equation:

In the above equation R may represent any of radicals characteristic of steroids having substituents in the 17 position such as COCHs, COCI-IzOAC, R is the residue of a mercaptan such as the benzyl radical, the ethyl radical etc. Although the M-3 keto group is given by way of example above, other groupings in rings A, B and C may be present such as the 11 keto group or the esterified 3 3 hydroxy group and -6 double bond characteristic of pregnenolone acetate.

In preparing the 16 thio derivatives referred to above the process set for in the aforementioned prior application is suitable, the steroid being dissolved in a suitable solvent and refluxed with the mercaptan and a catalyst such as pyridine.

The thio group can be removed from the 16-thio compounds previously referred to by reacting the 16-thio compounds with Raney nickel. Thus upon reaction of, for example, 3-acetoxypregnenolone-16-thioacetic acid with Raney nickel as by refluxing in a suitable solvent, such as acetone, pregnenolone acetate is produced. Similarly the reaction of A -pregnene-16-thioacetic acid with Raney nickel produced progesterone. Similarly other 16-thio compounds can be desulfurized with Raney nickel without afiecting double bonds in rings A or B or other functional groups in rings A, B or C and the 2,702,297 Patented reb. 15, 1955 process is therefore generally applicable to the production of compounds of the pregnene, pregnane or allopregnane series from the corresponding lo-dehydro compounds. Further, the method can also be used in the case of 1,6-dehydro compounds containing the cortico steroidal side chain at 17. v

The followingspecific examples serve to illustrate but are not intended to limit the present invention:

Example I -A solution of 5 g. of A 16 pregnadien-3fl oh20-one S acetat'e in 150 ee t benzene was refluxed during 5 hours with,5 g. of'fi mercap'toethanol and '6 cc. of piperidine. After 20 hours" at room' temperature; the reaction mixture was washed with dilute hydrochloric acid and with water, dried and evaporated to dryness.' One crystallization fromether'pentane aifordd of 16 (fi-hydroxye'thylmerca'pto.) A pregtien-saoi-zo ene 3 acetate; melting point 91-93 C., (dob- "24;5 (di- 'oxane). v 7

Example 11 2 g. .of the product obtainedaccording to Example I, was refluxed inac'etone solution for 3 hours with 20 g. of Raney nickel. The catalyst'was filteredand the solution evaporated to dryness. One crystallization from ethylacetate gaye in 52% yield A -pregnen-3B-ol-20-one S-acetate; melting point 147-148 C., (00 14 (chloroform).

Example III A solution of 5 g. of h -pregnadien-3,20-dione was treated in exactly the same rnane'r as described in Example I. one crystallization from methanol afiorded 92% of 16 (B 7 hydroxyethylmercapto)progesterone; melting point 72-74" C., (ud +8 1 (dioxane).

Example 1V An acetone solution of 2 g. of the product obtained according to Example III was treated in the same way as described in Example II, yielding after one crystallization gl'zo7l'nlllgghll0l, 60% of progesterone with melting point Example V An acetone solution of 2 g. of 16-thiobenzylprogesterone, obtained according to the method set forth in United States application Serial No. 206,726, was treated exactly as described in Example II; after one crystallization from methanol, progesterone was obtained in 63% yield; melting point 127-129 C.

Example VI 6 g. of A -pregnadiene-3,B-Ol-ZO-one acetate and 6 cc. of thioglycolic acid were dissolved in 210 cc. of benzene. After distilling 60 cc. of benzene, 7 cc. of piperidine were added and the solution was refluxed for 5 hours. The mixture was washed with water and then with dilute hydrochloric acid to remove the piperidine. The product was extracted with three portions of saturated sodium carbonate solution and the alkaline solution was acidified with hydrochloric acid to precipitate the product which was filtered after a few hours, washed and dried. It yielded 5.5 g. of 3-acetoxy-pregnenolone-1o-thioacetic acid; melting point ISO-182 C., ((1) -37 (dioxane).

For further identification of the product, a methyl ester was prepared by esterification with diazomethane by known methods. The methyl ester of 3-acetoxy-pregnenolone-16-thioacetic acid had melting point 136-138 C., -20 (dioxane).

Example VII 20 g. of Raney nickel were added to a solution of 1 g. of 3-acetoxypregnenolone-l6-thioacetic acid in cc. of acetone and the mixture was refluxed during 2 hours. The catalyst was removed by filtration and the solution was evaporated to dryness. Crystallization of the residue from methanol yielded 600 mg. of pregnenolone acetate with melting point 140-144" C., (00 -17 (chloroform).

Example VIII A solution of 10 g. of 'A -pregnadiene-3,20-dione- Example IX 2 g. of the oil obtained according to Example VIII were dissolved in acetone and treated in exactly the same way as described in Example VII. One recrystallization of the product from methanol aiforded 63% of progesterone; melting point 126-128.'

We claim:

1. A process for the production of 16-saturated steroids of the pregnene series from corresponding 16- dehydrosteroids of the pregnene series which comprises reacting said 16-dehydrosteroid with a mercaptan in the presence of a catalyst to form the corresponding 16-thiosteroid and refluxing said 16-thiosteroid in the presence of Raney nickel catalyst.

2. The process of claim 1 wherein the steroid is 16- dehydroprogesterone, the mercaptan is ;3-mercaptoethanol and the catalyst is piperidine.

3. The process of claim 1 wherein the steroid is A -pregnadien-3p-ol-20-one 3 acetate, the mercaptan is B-mercaptoethanol and the catalyst is piperidine.

4. The process of claim 1 wherein the steroid is 16- dehydroprogesterone, the mercaptan is thioglycolic acid and the catalyst is piperidine.

5. The process of claim 1 wherein the steroid is A pregnadien-3fi-ol-20-one 3 acetate, the mercaptan is thioglycolic acid and the catalyst is piperidine.

6. A new compound consisting of IG-(B-hydroxyethylmercapto)-A -pregnen-3fl-ol-20-one 3-acetate having a melting point of 91-93 C.

7. A new compound consisting of l-(fi-hydroxyetzhyllzl erccaptoyprogesterone having a melting point of 8. A new compound consisting of 3-acet0xypregnen'o- V 4 lgngI-thioacietic acid having a melting point of 9. A new compound consisting of A -pregnen-3,20'-dione-lfi-thioacetic acid.

10. A new compound selected from the group consisting of compounds of the following formula:

and

whgrein X is selected from the group consisting of 0:0 an

and SR is selected from the group consisting of the residue of fl-mercaptoethanol and thioglycolic acid.

No references cited. 

1. A PROCESS FOR THE PRODUCTION OF 16-SATURATED STEROIDS OF THE PREGNENE SERIES FROM CORRESPONDING 16DEHYDROSTERIODS OF THE PREGENE SERIES WHICH COMPRISES REACTING SAID 16-DEHYDROSTEROID WITH A MERCAPTAN IN THE PRESENCE OF A CATALYST TO FORM THE CORRESPONDING 16-THIOSTEROID AND REFLUXING SAID 16-THIOSTEROID IN THE PRESENCE OF RANEY NICKEL CATALYST. 